Thoracic aortic aneurysm (TAA) disease is a potentially devastating disease process which often causes death by rupture in the absence of symptoms. TAA formation proceeds by a multifactorial process, influenced by both cellular and extracellular mechanisms that result in alterations of the structure and composition of the extracellular matrix (ECM). There are currently no effective non-surgical clinical treatment protocols available which will halt or reverse the aortic remodeling process during aneurysm formation. While current data demonstrate that this pathological remodeling is a result of a significant spatiotemporal change in the expression/abundance of the matrix metalloproteinases and their endogenous tissue inhibitors, little attention has been focused on the upstream signaling events that regulate the remodeling process. One upstream signaling protein known to alter the structure and composition of the ECM, and known to play an important role in vascular remodeling is transforming growth factor-beta (TGF-b). Examination of the TGF-b signaling pathway during TAA development revealed a shift in signaling from a TGF-bRI-mediated pathway to an ALK-1- mediated pathway. Accordingly, the present proposal will test the central hypothesis that signaling through the ALK-1 pathway drives aberrant vascular remodeling and TAA development. Using a small animal model of TAA, cellular studies of isolated aortic fibroblasts, and in vivo delivery of specific genes/inhibitors, this hypothesis will be tested by: (1) establishing the relationship between alterations in TGF-b signaling and changes in the determinants of ECM degradation/deposition during TAA development;(2) demonstrating that alterations in MMP/TIMP expression and abundance are mediated by the effects of TGF-b on aortic fibroblasts;and (3) demonstrating that MMP/TIMP abundance and aortic dilatation can be altered by modifying TGF-b signaling in vivo. This unique set of proposed studies will establish the relationship between altered TGF-b signaling and the production of the degradative determinants of ECM remodeling. The outcomes of this proposal will provide exceptional insight into the development of TAA and may identify significant targets through which TAA formation and progression can be disrupted. PUBLIC HEALTH RELEVANCE: Thoracic aortic aneurysm (TAA) disease is a potentially devastating disease process which often lacks specific symptomology, rendering them unnoticed until the aorta ruptures, resulting in significant morbidity and mortality. Currently, there are no noninvasive interventional treatments available for TAA patients. A "watch and wait" surveillance program is initiated until the risk of aortic rupture outweighs the risk of the surgical repair. With a growing concern of increased aneurysm incidence due to a rapidly aging Veterans population and a high prevalence for cardiovascular disease, further diagnostic and therapeutic advancement is critical. The present proposal will assess key components of the TGF-b signaling pathway, in an effort to understand the role of TGF-b signaling in the etiology of TAA disease. Elucidating the underlying mechanisms may assist in developing strategies to arrest TAA formation or even reverse TAA progression, and will carry significant diagnostic, prognostic, and therapeutic implications for Veteran's and the public at large.